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Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling.

BACKGROUND: Abnormal diastolic function is an independent predictor of adverse postoperative outcomes. Mitral annular tissue Doppler velocity (e) is a key parameter for assessing diastolic function. The purpose of this study was to confirm that an acute increase in preload did not significantly impact the intraoperative measurement of e and secondarily evaluate the impact of this acute intravascular volume increase on the clinical assessment of diastolic function using a previously described simplified algorithm. METHODS: This was a prospective, non-randomized study in adult patients undergoing elective cardiac surgeries requiring transesophageal echocardiographic monitoring, arterial pressure and Swan-Ganz catheter placements as part of the surgical procedure. Following baseline echocardiographic and hemodynamic measurements, 500 ml of crystalloid solution was infused over 10 min. Hemodynamic and echocardiographic measurements were repeated 5 min after fluid administration. RESULTS: Complete data sets were available from 84 of the 100 patients who were enrolled in this study. There was no significant change in the values of e. The average baseline was 7.8 ± 2.0 cm/s (95%CI: 7.4, 8.2) and 8.1 ± 2.4 (95%CI: 7.6, 8.6) following the fluid bolus (p = 0.10). All hemodynamic variables associated with increased intravascular volume (central venous pressure, pulmonary arterial pressures and stroke volume variation) changed significantly. The overall distribution of diastolic function grades did not change following fluid administration (p = 0.69). However, there were many individual patient differences. When using this simplified algorithm, functional grading changed in 35 patients. Thirty of these 35 changes were only a single grade shift. 22 patients had worse functional grading after fluid administration while 13 had improved grading. Nine patients with normal diastolic function at baseline demonstrated diastolic dysfunction after fluid administration while 6 patients with baseline dysfunction normalized following the fluid bolus. CONCLUSION: We confirmed that e is a robust measurement that is reproducible in the intraoperative setting despite variable vascular volume loading conditions, however, the clinical assessment of diastolic function was still altered in 42% of the patients following an intravenous fluid bolus.

The Japanese national guidelines recommend significantly lower doses of carvedilol for heart failure with reduced ejection fraction (HFrEF) management than the US guidelines. Using real-world data, we determined whether initial and target doses of carvedilol in Japanese patients (JPNs) differ from those in US patients (USPs), especially in Asian Americans (ASA) and Caucasians (CA), and investigated differences in outcomes. We collected data from the electronic medical records, including demographics, carvedilol dosing, tolerability, cardiac functional indicators like EF, cardiovascular events including all-cause deaths, and laboratory values from the University of California, San Diego Health and Osaka University. JPNs had significantly lower doses (mg/day) of carvedilol initiation (66 USPs composed of 38 CAs and 28 ASAs, 17.1±16.2; 93 JPNs, 4.3±4.2, p

BACKGROUND: Central sleep apnea (CSA) is associated with increased mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Treatment of CSA with a certain type of adaptive servo-ventilation (ASV) device that targets minute ventilation (ASVmv) was found to be harmful in these patients. A newer generation of ASV devices that target peak flow (ASVpf) is presumed to have different effects on ventilation and airway patency. We analyzed our registry of patients with HFrEF-CSA to examine the effect of exposure to ASV and role of each type of ASV device on mortality. METHODS: This is a retrospective cohort study in patients with HFrEF and CSA who were treated with ASV devices between 2008 and 2015 at a single institution. Mortality data were collected through the institutional data honest broker. Usage data were obtained from vendors and manufacturers servers. Median follow-up was 64 months. RESULTS: The registry included 90 patients with HFrEF-CSA who were prescribed ASV devices. Applying a 3-h-per-night usage cutoff, we found a survival advantage at 64 months for those who used the ASV device above the cutoff (n = 59; survival 76%) compared to those who did not (n = 31; survival 49%; hazard ratio 0.44; CI 95%, 0.20 to 0.97; P = 0.04). The majority (n = 77) of patients received ASVpf devices with automatically adjusting end-expiratory pressure (EPAP) and the remainder (n = 13) received ASVmv devices mostly with fixed EPAP (n = 12). There was a trend towards a negative correlation between ASVmv with fixed EPAP and survival. CONCLUSION: In this population of patients with HFrEF and CSA, there was no evidence that usage of ASV devices was associated with increased mortality. However, there was evidence of differential effects of type of ASV technology on mortality.

BACKGROUND: Left ventricular (LV) systolic dysfunction is associated with a >8-fold increased risk of heart failure and a 2-fold risk of premature death. The use of ECG signals in screening for LV systolic dysfunction is limited by their availability to clinicians. We developed a novel deep learning-based approach that can use ECG images for the screening of LV systolic dysfunction. METHODS: Using 12-lead ECGs plotted in multiple different formats, and corresponding echocardiographic data recorded within 15 days from the Yale New Haven Hospital between 2015 and 2021, we developed a convolutional neural network algorithm to detect an LV ejection fraction 27-fold higher odds of LV systolic dysfunction on transthoracic echocardiogram (odds ratio, 27.5 [95% CI, 22.3-33.9] in the held-out set). Class-discriminative patterns localized to the anterior and anteroseptal leads (V2 and V3), corresponding to the left ventricle regardless of the ECG layout. A positive ECG screen in individuals with an LV ejection fraction ≥40% at the time of initial assessment was associated with a 3.9-fold increased risk of developing incident LV systolic dysfunction in the future (hazard ratio, 3.9 [95% CI, 3.3-4.7]; median follow-up, 3.2 years). CONCLUSIONS: We developed and externally validated a deep learning model that identifies LV systolic dysfunction from ECG images. This approach represents an automated and accessible screening strategy for LV systolic dysfunction, particularly in low-resource settings.

BackgroundHeart failure with reduced ejection fraction (HFrEF) is one of the most costly and deadly chronic disease states. The cost effectiveness of a comprehensive quadruple therapy regimen for HFrEF has not been studied.ObjectivesThe authors sought to determine the cost-effectiveness of quadruple therapy comprised of beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium glucose cotransporter-2 inhibitors vs regimens composed of only beta-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists (triple therapy), and angiotensin-converting enzyme inhibitors and beta-blockers (double therapy).MethodsUsing a 2-state Markov model, the authors performed a cost-effectiveness study using simulated populations of 1,000 patients with HFrEF based on the participants in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial and compared them by treatment strategy (quadruple therapy vs triple and double therapy) from a United States health care system perspective. The authors also performed 10,000 probabilistic simulations.ResultsTreatment with quadruple therapy resulted in an increase of 1.73 and 2.87 life-years compared with triple therapy and double therapy, respectively, and an increase in quality-adjusted life-years of 1.12 and 1.85 years, respectively. The incremental cost-effectiveness ratios of quadruple therapy vs triple therapy and double therapy were $81,000 and $51,081, respectively. In 91.7% and 99.9% of probabilistic simulations quadruple therapy had an incremental cost-effectiveness ratio of

BackgroundAfterload from moderate aortic stenosis (AS) may contribute to adverse outcomes in patients with heart failure with reduced ejection fraction (HFrEF).ObjectivesThe authors evaluated clinical outcomes in patients with HFrEF and moderate AS relative to those without AS and with severe AS.MethodsPatients with HFrEF, defined by left ventricular ejection fraction (LVEF)

AimsHeart disease is associated with an increased risk for ischaemic stroke. However, the predictive value of reduced left ventricular ejection fraction (LVEF) for stroke is controversial and only observed in patients with severe reduction. LV global longitudinal strain (LV GLS) can detect subclinical LV systolic impairment when LVEF is normal. We investigated the prognostic role of LV GLS for incident stroke in a predominantly elderly cohort.Methods and resultsTwo-dimensional echocardiography with speckle tracking was performed in the Cardiac Abnormalities and Brain Lesions (CABL) study. Among 708 stroke-free participants (mean age 71.4 ± 9.4 years, 60.9% women), abnormal LV GLS (>-14.7%: 95% percentile of the subgroup without risk factors) was detected in 133 (18.8%). During a mean follow-up of 10.8 ± 3.9 years, 47 participants (6.6%) experienced an ischaemic stroke (26 cardioembolic or cryptogenic, 21 other subtypes). The cumulative incidence of ischaemic stroke was significantly higher in participants with abnormal LV GLS than with normal LV GLS (P < 0.001). In multivariate stepwise logistic regression analysis, abnormal LV GLS was associated with ischaemic stroke independently of cardiovascular risk factors including LVEF, LV mass, left atrial volume, subclinical cerebrovascular disease at baseline, and incident atrial fibrillation [hazard ratio (HR): 2.69, 95% confidence interval (CI): 1.47-4.92; P = 0.001]. Abnormal LV GLS independently predicted cardioembolic or cryptogenic stroke (adjusted HR: 3.57, 95% CI: 1.51-8.43; P = 0.004) but not other subtypes.ConclusionLV GLS was a strong independent predictor of ischaemic stroke in a predominantly elderly stroke-free cohort. Our findings provide insights into the brain-heart interaction and may help improve stroke primary prevention strategies.

Right ventricular (RV) function is an important marker of mortality in chronic left-sided heart failure. Right ventricular function is particularly important for patients receiving left ventricular assist devices as it is a predictor of postoperative RV failure. RV stroke work index (RVSWI), the area enclosed by a pressure-volume (PV) loop, is prognostic of RV failure. However, clinical RVSWI approximates RVSWI as the product of thermodilution-derived stroke volume and the pulmonary pressure gradient. This ignores the energetic contribution of regurgitant flow and does not allow for advanced energetic measures, such as pressure-volume area and efficiency. Estimating RVSWI from forward flow may underestimate the underlying RV function. We created single-beat PV loops by combining data from cine computed tomography (CT) and right heart catheterization in 44 heart failure patients, tested the approximations made by clinical RVSWI and found it to underestimate PV loop RVSWI, primarily due to regurgitant flow in tricuspid regurgitation. The ability of RVSWI to predict post-operative RV failure improved when the single-beat approach was used. Further, RV pressure-volume area and efficiency measures were obtained and show broad agreement with other functional measures. Future work is needed to investigate the utility of these PV metrics in a clinical setting.

Human immunodeficiency virus (HIV) infection is associated with subclinical cardiomyopathy, diastolic dysfunction, and increased risk of cardiovascular death. However, the relationship between left atrial (LA) mechanics and left ventricular (LV) diastolic function has not been evaluated in people living with HIV (PLWH) relative to HIV-uninfected (HIV-) controls. This is a multicenter, cross-sectional cohort analysis using the HIV Cardiovascular Disease substudy of the Veterans Aging Cohort Study database, which aimed to examine a cohort of PLWH and HIV- veterans without known cardiovascular disease. A total of 277 subjects (180 PLWH, 97 HIV-) with echocardiograms were identified. LV and LA phasic strain were derived and diastolic function was evaluated. Relationship between LA strain, LV strain, and the degree of diastolic dysfunction were assessed using analysis of variance and ordinal logistic regression with propensity weighting. In the PLWH cohort, 91.7% were on antiretroviral therapy and 86.1% had HIV viral loads

Identification of patients who are at a high risk for right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation is of critical importance. Conventional tools for predicting RVF, including two-dimensional echocardiography, right heart catheterization (RHC), and clinical parameters, generally have limited sensitivity and specificity. We retrospectively examined the ability of computed tomography (CT) ventricular volume measures to identify patients who experienced RVF after LVAD implantation. Between September 2017 and November 2021, 92 patients underwent LVAD surgery at our institution. Preoperative CT-derived ventricular volumes were obtained in 20 patients. Patients who underwent CT evaluation had a similar demographics and rate of RVF after LVAD as patients who did not undergo cardiac CT imaging. In the study cohort, seven of 20 (35%) patients experienced RVF (2 unplanned biventricular assist device, 5 prolonged inotropic support). Computed tomography-derived right ventricular end-diastolic and end-systolic volume indices were the strongest predictors of RVF compared with demographic, echocardiographic, and RHC data with areas under the receiver operating curve of 0.79 and 0.76, respectively. Computed tomography volumetric assessment of RV size can be performed in patients evaluated for LVAD treatment. RV measures of size provide a promising means of pre-LVAD assessment for postoperative RV failure.

AIM: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

IntroductionThe antibody-drug conjugate trastuzumab deruxtecan (T-DXd) targets human epidermal growth factor receptor 2 (HER2) and has been evaluated in patients with HER2-positive unresectable/metastatic breast cancer in the phase II DESTINY-Breast01 trial (NCT03248492; DS8201-A-U201) and the randomized phase III DESTINY-Breast03 trial (NCT03529110; DS8201-A-U302). Approximately 20 additional studies are ongoing in breast cancer, including HER2-low breast cancer, and other solid tumor types within the DESTINY trial program. T-DXd has demonstrated a generally manageable safety profile, with low-grade hematologic and gastrointestinal adverse events (AEs) among the most common; interstitial lung disease (ILD)/pneumonitis has been observed in patients receiving T-DXd and can be severe. This review discusses the management of common AEs and AEs of special interest in patients with HER2-positive unresectable/metastatic breast cancer, including nausea and vomiting, neutropenia, infusion-related reactions, alopecia, fatigue, ILD/pneumonitis, and left ventricular dysfunction.MethodsExpert opinions, institutional protocols, and strategies to help optimize AE management and maximize the potential benefits of T-DXd in patients with breast cancer from five oncologists treating patients with T-DXd in North America and Europe are discussed.ResultsProphylaxis for nausea and vomiting and proactive management of ILD/pneumonitis are especially important in treating patients with T-DXd. Management strategies for other T-DXd-related AEs of interest (e.g. neutropenia, infusion-related reactions, alopecia, fatigue, and left ventricular dysfunction) are also discussed.ConclusionsThis review provides context for understanding the usage, monitoring, and management practices of other health care providers and institutions with experience using T-DXd to help with safe and effective management of T-DXd-related AEs, particularly since the duration of T-DXd treatment may be quite long. Proper management of T-DXd-related AEs will allow optimal exposure and benefit from T-DXd and will help avoid premature discontinuation or improper dose reductions.

BackgroundTranscatheter mitral valve repair is beneficial in patients with mitral regurgitation (MR), left ventricular dysfunction, and persistent symptoms despite maximally tolerated medical therapy.ObjectivesThe aim of this study was to evaluate the safety and feasibility of transcatheter mitral cerclage ventriculoplasty in patients with MR and either heart failure with reduced ejection fraction or preserved ejection fraction and in subjects with prior edge-to-edge repair but persistent or recurrent symptomatic MR.MethodsThe National Heart, Lung, and Blood Institute Division of Intramural Research Transcatheter Mitral Cerclage Ventriculoplasty Early Feasibility Study (NCT03929913) was an investigator-initiated prospective multicenter study. The primary endpoint was technical success measured at exit from the catheterization laboratory. Follow-up included heart failure quality-of-life assessments and serial imaging with echocardiography and cardiac computed tomography.ResultsNineteen subjects consented and underwent cerclage, 63% with heart failure with reduced ejection fraction and 37% with heart failure with preserved ejection fraction, with ischemic cardiomyopathy in 26% and nonischemic cardiomyopathy in 74%. There were no procedural deaths, strokes, or transient ischemic attacks or other major cardiovascular adverse events. The primary endpoint was met in 17 subjects. Cerclage induced sustained reductions in mitral regurgitant volume (-41%) and effective orifice area (-33%) after a median of 337 days. Cerclage resulted in improvements in 6-minute walking distance (+78 m) and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (+22 points) at 30 days that were maintained after a median of 265 days. New complete heart block developed in 6 of 17 subjects. Three deaths occurred on postprocedural days 79, 159, and 756, unrelated to cerclage.ConclusionsTranscatheter mitral cerclage ventriculoplasty resulted in significant and sustained improvements in mitral regurgitation and in heart failure quality-of-life assessments.

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Background and objectiveThe goal of this work was to determine whether midlife cardiac structure and function and their 25-year change from early to middle adulthood are associated with lower midlife cognition.MethodsWe studied 2,653 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study (57% women, 46% Black). Echocardiograms were obtained at year 5, 25, and 30 visits (participant mean age 30, 50, and 55 years) to assess left ventricular (LV) mass (LVM), LV systolic function with LV ejection fraction (LVEF), and LV diastolic function with left atrial volume (LAV) and early peak mitral velocity (E)/early peak mitral annular velocity (e') ratio. LVM and LAV were indexed to body surface area (LVMi and LAVi). At year 30, 5 cognitive domains were measured: global cognition, processing speed, executive function, delayed verbal memory, and verbal fluency. We investigated the association between midlife (year 30) and 25-year change in cardiac structure and function on midlife cognition using linear regressions.ResultsOver 25 years, LVMi and LAVi increased with mean change (SD) per year of 0.27 (0.28) g/m2 and 0.42 (0.15) mL/m2, while LVEF decreased by 0.11% (0.02%). After adjustment for demographics and education, 25-year increase (≥1 SD) in LVMi was associated with lower cognition on most tests (p ≤ 0.02); 25-year increase in LAVi was associated with lower global cognition (p = 0.04), but 25-year decrease in LVEF was not associated with cognition. Further adjustment for cardiovascular risk factors led to similar results. In addition, unlike year 30 E/e' ratio and LVEF, higher year 30 LVMi and LAVi were significantly associated with worse cognition on most cognitive tests.DiscussionMidlife cardiac structure and its change from early to middle adulthood are associated with lower midlife cognition even after accounting for confounders. Unlike systolic function, midlife LV diastolic function and its 25-year change were also linked to cognition. Our results provide information linking early to midlife cardiac structure and function to cognition.

BackgroundWe aimed to evaluate for occult systolic dysfunction and the effect of methamphetamine cessation among patients with methamphetamine use (MU) and heart failure with preserved ejection fraction (HFpEF).MethodsA retrospective cohort of patients with HFpEF with serial echocardiograms was stratified by MU and evaluated using myocardial strain analysis on echocardiograms at baseline and 1 year to measure global longitudinal strain (GLS). Contemporaneous controls with an ICD diagnosis of HF within 3 days of an MU case were chosen.ResultsPatients with MU (n = 31) were younger (49 ± 10 vs 59 ± 16 years, p

In-vivo studies of pulmonary vascular disease and pulmonary hypertension (PH) have provided key insight into the progression of right ventricular (RV) dysfunction. Additional in-silico experiments using multiscale computational models have provided further details into biventricular mechanics and hemodynamic function in the presence of PH, yet few have assessed whether model parameters are practically identifiable prior to data collection. Moreover, none have used modeling to devise synergistic experimental designs. To address this knowledge gap, we conduct a practical identifiability analysis of a multiscale cardiovascular model across four simulated experimental designs. We determine a set of parameters using a combination of Morris screening and local sensitivity analysis, and test for practical identifiability using profile likelihood-based confidence intervals. We employ Markov chain Monte Carlo (MCMC) techniques to quantify parameter and model forecast uncertainty in the presence of noise corrupted data. Our results show that model calibration to only RV pressure suffers from practical identifiability issues and suffers from large forecast uncertainty in output space. In contrast, parameter and model forecast uncertainty is substantially reduced once additional left ventricular (LV) pressure and volume data is included. A comparison between single point systolic and diastolic LV data and continuous, time-dependent LV pressure-volume data reveals that at least some quantitative data from both ventricles should be included for future experimental studies.

Primary cardiac involvement is one of the leading causes of mortality in systemic sclerosis (SSc), but little is known regarding circulating biomarkers for cardiac SSc. Here, we aimed to investigate potential associations between cardiac SSc and candidate serum markers. Serum samples from patients of the Oslo University SSc cohort and 100 healthy controls were screened against two custom-made candidate marker panels containing molecules deemed relevant for cardiopulmonary and/or fibrotic diseases. Left (LV) and right ventricular (RV) dysfunction was assessed by protocol echocardiography, performed within three years from serum sampling. Patients suspected of pulmonary hypertension underwent right heart catheterization. Vital status at study end was available for all patients. Descriptive analyses, logistic and Cox regressions were conducted to assess associations between cardiac SSc and candidate serum markers. The 371 patients presented an average age of 57.2 (± 13.9) years. Female sex (84%) and limited cutaneous SSc (73%) were predominant. Association between LV diastolic dysfunction and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR 0.41, 95% CI 0.21-0.78, p = 0.007) was identified. LV systolic dysfunction defined by global longitudinal strain was associated with angiopoietin 2 (ANGPT2) (OR 3.42, 95% CI 1.52-7.71, p = 0.003) and osteopontin (OPN) (OR 1.95, 95% CI 1.08-3.52, p = 0.026). RV systolic dysfunction, measured by tricuspid annular plane systolic excursion, was associated to markers of LV dysfunction (ANGPT2, OPN, and TRAIL) (OR 1.67, 95% CI 1.11-2.50, p = 0.014, OR 1.86, 95% CI 1.25-2.77, p = 0.002, OR 0.32, 95% CI 0.15-0.66, p = 0.002, respectively) and endostatin (OR 1.86, 95% CI 1.22-2.84, p = 0.004). In conclusion, ANGPT2, OPN and TRAIL seem to be circulating biomarkers associated with both LV and RV dysfunction in SSc.

Patients with heart failure (HF) and coronary artery disease (CAD) have a high risk for cardiovascular (CV) events including HF hospitalization, stroke, myocardial infarction (MI) and sudden cardiac death (SCD). The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case-control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR  0.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033-0.082), p

BACKGROUND: In ≈25% of patients with heart failure and reduced left-ventricular ejection fraction, right-ventricular (RV), and left-ventricular (LV) filling pressures are discordant (ie, one is elevated while the other is not). Whether clinical assessment allows detection of this discordance is unknown. We sought to determine the agreement of clinically versus invasively determined patterns of ventricular congestion. METHODS: In 156 heart failure and reduced LV ejection fraction subjects undergoing invasive hemodynamic assessment, we categorized patterns of ventricular congestion (no congestion, RV only, LV only, or both) based on clinical findings of RV (jugular venous distention) or LV (hepatojugular reflux, orthopnea, or bendopnea) congestion. Agreement between clinically and invasively determined (RV congestion if right atrial pressure [RAP] ≥10 mm Hg and LV congestion if pulmonary capillary wedge pressure [PCWP] ≥22 mm Hg) categorizations was the primary end point. RESULTS: The frequency of clinical patterns of congestion was: 51% no congestion, 24% both RV and LV, 21% LV only, and 4% RV only. Jugular venous distention had excellent discrimination for elevated RAP (C=0.88). However, agreement between clinical and invasive congestion patterns was poor, к=0.44 (95% CI, 0.34-0.55). While those with no clinical congestion usually had low RAP and PCWP (67/79, 85%), over one-half (24/38, 64%) with isolated LV clinical congestion had PCWP

Sodium-glucose cotransporter-2 inhibitor therapy is well suited for initiation during the heart failure hospitalization, owing to clinical benefits that accrue rapidly within days to weeks, a strong safety and tolerability profile, minimal to no effects on blood pressure, and no excess risk of adverse kidney events. There is no evidence to suggest that deferring initiation to the outpatient setting accomplishes anything beneficial. Instead, there is compelling evidence that deferring in-hospital initiation exposes patients to excess risk of early postdischarge clinical worsening and death. Lessons from other heart failure with reduced ejection fraction therapies highlight that deferring initiation of guideline-recommended medications to the U.S. outpatient setting carries a >75% chance they will not be initiated within the next year. Recognizing that 1 in 4 patients hospitalized for worsening heart failure die or are readmitted within 30 days, clinicians should embrace the in-hospital period as an optimal time to initiate sodium-glucose cotransporter-2 inhibitor therapy and treat this population with the urgency it deserves.

BackgroundMany patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells.MethodsWe used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress.ResultsObese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH.ConclusionsIn heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.

Most cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility. In this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF

Background Tetralogy of Fallot with absent pulmonary valve is associated with high mortality, but it remains difficult to predict outcomes prenatally. We aimed to identify risk factors for mortality in a large multicenter cohort. Methods and Results Fetal echocardiograms and clinical data from 19 centers over a 10-year period were collected. Primary outcome measures included fetal demise and overall mortality. Of 100 fetuses, pregnancy termination/postnatal nonintervention was elected in 22. Of 78 with intention to treat, 7 (9%) died in utero and 21 (27%) died postnatally. With median follow-up of 32.9 months, no deaths occurred after 13 months. Of 80 fetuses with genetic testing, 46% had chromosomal abnormalities, with 22q11.2 deletion in 35%. On last fetal echocardiogram, at a median of 34.6 weeks, left ventricular dysfunction independently predicted fetal demise (odds ratio [OR], 7.4; 95% CI 1.3, 43.0; P=0.026). Right ventricular dysfunction independently predicted overall mortality in multivariate analysis (OR, 7.9; 95% CI 2.1-30.0; P=0.002). Earlier gestational age at delivery, mediastinal shift, left ventricular/right ventricular dilation, left ventricular dysfunction, tricuspid regurgitation, and Doppler abnormalities were associated with fetal and postnatal mortality, although few tended to progress throughout gestation on serial evaluation. Pulmonary artery diameters did not correlate with outcomes. Conclusions Perinatal mortality in tetralogy of Fallot with absent pulmonary valve remains high, with overall survival of 64% in fetuses with intention to treat. Right ventricular dysfunction independently predicts overall mortality. Left ventricular dysfunction predicts fetal mortality and may influence prenatal management and delivery planning. Mediastinal shift may reflect secondary effects of airway obstruction and abnormal lung development and is associated with increased mortality.

Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the in vivo environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.

PurposeCardiotoxicity from anti-human epidermal growth factor receptor 2 (HER2) therapy carries a short- and long-term risk of incident heart failure and increased cardiovascular mortality in patients with breast cancer. Interruptions in anti-HER2 therapy due to cardiotoxicity can lead to suboptimal cancer treatment. The purpose of this narrative review is to outline opportunities to optimize cardiovascular care in patients with HER2-positive breast cancer to prevent interruptions in therapy.MethodsThis case-based review presents the current literature on evidence-based strategies for personalized cardiotoxicity risk assessment, risk mitigation interventions, cardiac function surveillance tools, and management of asymptomatic left ventricular dysfunction in breast cancer patients receiving anti-HER2 therapy.ResultsPretreatment cardiac risk assessment incorporates both treatment-related risk factors and patient-related risk factors for the development of cardiac dysfunction. Prevention and monitoring strategies while on treatment utilize risk factor modification, imaging and biomarker surveillance. Management of asymptomatic left ventricular dysfunction due to anti-HER2 therapy is evolving. Permissive cardiotoxicity in asymptomatic patients while starting cardioprotective therapies requires close collaboration between oncology and cardiology, and referral to cardio-oncology if available.ConclusionsPatient-centered, multimodal strategies to prevent, detect, and manage cardiotoxicity from anti-HER2 therapy are necessary to improve outcomes in patients with HER2-positive breast cancer.

ObjectivesThe radial artery pulse waveform is a continuous measure of pressure throughout the cardiac cycle, and thus can provide more information than just systolic and diastolic blood pressures. New indices based on a Windkessel model of the waveform, PTC1 and PTC2, are related to arterial compliance and add information for prediction of incident cardiovascular disease (coronary heart disease, stroke, myocardial infarction) but their association with heart failure is unknown.MethodsAmong 6229 adults (mean age 62 years) from four race/ethnic groups who were initially free of clinical cardiovascular disease and heart failure in 2000-2002, we evaluated the associations of baseline PTC1 and PTC2 with incident heart failure.ResultsMean ± standard deviation PTC1 and PTC2 were 394 ± 334 and 94 ± 46 ms, respectively. During a median of 15.7 years follow-up, there were 357 heart failure events (148 with reduced, 150 with preserved, and 59 with unknown ejection fraction). After adjustment for traditional risk factors, the hazard ratio for heart failure per 1 standard deviation higher PTC2 was 0.73 (95% confidence interval: 0.63--0.85). Higher PTC2 was also significantly associated with lower risk of heart failure with reduced ejection fraction (hazard ratio = 0.67; 95% confidence interval: 0.56--0.80). There was no evidence of a significant association between PTC2 and heart failure with preserved ejection fraction or between PTC1 and heart failure.ConclusionThe PTC2 measure of the radial artery pulse waveform may represent a novel phenotype related to heart failure, especially heart failure with reduced ejection fraction.

ObjectivesSeptic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy.DesignRetrospective cohort study.SettingAdult ICU.PatientsAdult ICU patients with sepsis.InterventionsNone.Measurements and main resultsLeft ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was -16.8% (interquartile range, -20.4% to -12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5.ConclusionsAmong patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials.

BackgroundRight ventricular (RV) dysfunction is a significant prognostic determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Despite the importance of RV function in PAH, the underlying molecular mechanisms of RV dysfunction secondary to PAH remain unclear. We aim to identify and compare molecular determinants of RV failure using RNA sequencing of RV tissue from 2 clinically relevant animal models of PAH.MethodsWe performed RNA sequencing on RV from rats treated with monocrotaline or Sugen with hypoxia/normoxia. PAH and RV failure were confirmed by catheterization and echocardiography. We validated the RV transcriptome results using quantitative real-time polymerase chain reaction, immunofluorescence, and Western blot. Immunohistochemistry and immunofluorescence were performed on human RV tissue from control (n=3) and PAH-induced RV failure patients (n=5).ResultsWe identified similar transcriptomic profiles of RV from monocrotaline- and Sugen with hypoxia-induced RV failure. Pathway analysis showed genes enriched in epithelial-to-mesenchymal transition, inflammation, and metabolism. Histological staining of human RV tissue from patients with RV failure secondary to PAH revealed significant RV fibrosis and endothelial-to-mesenchymal transition, as well as elevated cellular communication network factor 2 (top gene implicated in epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition) expression in perivascular areas compared with normal RV.ConclusionsTranscriptomic signature of RV failure in monocrotaline and Sugen with hypoxia models showed similar gene expressions and biological pathways. We provide translational relevance of this transcriptomic signature using RV from patients with PAH to demonstrate evidence of epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition and protein expression of cellular communication network factor 2 (CTGF [connective tissue growth factor]). Targeting specific molecular mechanisms responsible for RV failure in monocrotaline and Sugen with hypoxia models may identify novel therapeutic strategies for PAH-associated RV failure.

Right ventricular (RV) remodeling and longitudinal fiber reorientation in the setting of pulmonary hypertension (PH) affects ventricular structure and function, eventually leading to RV failure. Characterizing the kinematics of myocardial fibers helps better understanding the underlying mechanisms of fiber realignment in PH. In the current work, high-frequency ultrasound imaging and structurally-informed finite element (FE) models were employed for an exploratory evaluation of the stretch-induced kinematics of RV fibers. Image-based experimental evaluation of fiber kinematics in porcine myocardium revealed the capability of affine assumptions to effectively approximate myofiber realignment in the RV free wall. The developed imaging framework provides a noninvasive modality to quantify transmural RV myofiber kinematics in large animal models. FE modeling results demonstrated that chronic pressure overload, but not solely an acute rise in pressures, results in kinematic shift of RV fibers towards the longitudinal direction. Additionally, FE simulations suggest a potential protective role for concentric hypertrophy (increased wall thickness) against fiber reorientation, while eccentric hypertrophy (RV dilation) resulted in longitudinal fiber realignment. Our study improves the current understanding of the role of different remodeling events involved in transmural myofiber reorientation in PH. Future experimentations are warranted to test the model-generated hypotheses.

BackgroundThe prognostic value of right ventricular systolic dysfunction in high-risk patients undergoing non-emergent open abdominal surgery is unknown. Here, we aim to evaluate whether presence of preexisting right ventricular systolic dysfunction in this surgical cohort is independently associated with higher incidence of postoperative major adverse cardiac events and all-cause in-hospital mortality.MethodsThis is a single-centered retrospective study. Patients identified as American Society Anesthesiology Classification III and IV who had a preoperative echocardiogram within 1 year of undergoing non-emergent open abdominal surgery between January 2010 and May 2017 were included in the study. Incidence of postoperative major cardiac adverse events and all-cause in-hospital mortality were collected. Multivariable logistic regression was performed in a step-wise manner to identify independent association between preexisting right ventricular systolic dysfunction with outcomes of interest.ResultsPreexisting right ventricular systolic dysfunction was not associated with postoperative major adverse cardiac events (P = 0.26). However, there was a strong association between preexisting right ventricular systolic dysfunction and all-cause in-hospital mortality (P = 0.00094). After multivariate analysis, preexisting right ventricular systolic dysfunction continued to be an independent risk factor for all-cause in-hospital mortality with an odds ratio of 18.9 (95' CI: 1.8-201.7; P = 0.015).ConclusionIn this retrospective study of high-risk patients undergoing non-emergent open abdominal surgery, preexisting right ventricular systolic dysfunction was found to have a strong association with all-cause in-hospital mortality.

BackgroundPeople living with human immunodeficiency virus (PLWH) are at risk of developing pulmonary hypertension (PH) and right ventricular (RV) dysfunction, but understanding of the relationship of RV function to afterload (RV-PA coupling) is limited. We evaluated the clinical and hemodynamic characteristics of human immunodeficiency virus (HIV)-associated PH.MethodsWe performed a retrospective review of patients with a diagnosis of HIV undergoing right heart catheterization (RHC) from 2000-2016 in a tertiary care center. Inclusion criteria were diagnosis of HIV, age ≥ 18 years and availability of RHC data. PH was classified as either pulmonary arterial hypertension (PAH; mean pulmonary arterial pressure [mPAP] ≥ 25mmHg with pulmonary artery wedge pressure [PAWP] ≤ 15mmHg) or pulmonary venous hypertension (PVH; mPAP ≥ 25mmHg with PAWP > 15). We collected demographics, CD4 cell count, HIV viral load, RHC and echocardiographic data. The single beat method was used to calculate RV-PA coupling from RHC.ResultsSixty-two PLWH with a clinical likelihood for PH underwent RHC. Thirty-two (52%) met PH criteria (15 with PAH, 17 with PVH). Average time from diagnosis of HIV to diagnosis of PH was 11 years. Eleven of 15 individuals with PAH were on antiretroviral therapy (ART) while all 17 patients with PVH were on ART. Compared to PLWH without PH, those with PH had an increased likelihood of having a detectable HIV viral load and lower CD4 cell counts. PLWH with PAH or PVH had increased RV afterload with normal RV contractility, and preserved RV-PA coupling.ConclusionPLWH with PH (PAH or PVH) were more likely to have a detectable HIV viral load and lower CD4 count at the time of RHC. PLWH with PAH or PVH had increased RV afterload, normal RV contractility, with preserved RV-PA coupling suggestive of an early onset, mild, and compensated form of PH. These results should be confirmed in larger studies.

Trauma remains a leading global cause of mortality, particularly in the young population. In the United States, approximately 30,000 patients with blunt cardiac trauma were recorded annually. Cardiac damage is a predictor for poor outcome after multiple trauma, with a poor prognosis and prolonged in-hospitalization. Systemic elevation of cardiac troponins was correlated with survival, injury severity score, and catecholamine consumption of patients after multiple trauma. The clinical features of the so-called "commotio cordis" are dysrhythmias, including ventricular fibrillation and sudden cardiac arrest as well as wall motion disorders. In trauma patients with inappropriate hypotension and inadequate response to fluid resuscitation, cardiac injury should be considered. Therefore, a combination of echocardiography (ECG) measurements, echocardiography, and systemic appearance of cardiomyocyte damage markers such as troponin appears to be an appropriate diagnostic approach to detect cardiac dysfunction after trauma. However, the mechanisms of post-traumatic cardiac dysfunction are still actively being investigated. This review aims to discuss cardiac damage following trauma, focusing on mechanisms of post-traumatic cardiac dysfunction associated with inflammation and complement activation. Herein, a causal relationship of cardiac dysfunction to traumatic brain injury, blunt chest trauma, multiple trauma, burn injury, psychosocial stress, fracture, and hemorrhagic shock are illustrated and therapeutic options are discussed.

BackgroundGene regulatory networks control tissue homeostasis and disease progression in a cell type-specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown.MethodsWe combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis.ResultsHere, we show that cardiomyocyte-specific deletion of Brd4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators Ppargc1a, Ppargc1b, and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity.ConclusionsThese results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.

Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (P=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.

BackgroundDiastolic dysfunction (DD) is common and occurs at an earlier age among human immunodeficiency virus-infected (HIV+) individuals, but the mechanisms and consequences of DD among HIV+ individuals are unclear.Methods and resultsThe Characterization of Heart Function on Antiretroviral Therapy (CHART) study was a multicenter cross-sectional case-control study of treated and virally suppressed HIV+ individuals with (DD+) and without DD (DD-). All patients had normal ejection fraction (>50%), no significant valvular disease, and no history of coronary revascularization or persistent atrial fibrillation. Overall, 94 DD+ and 101 DD- patients were included. DD+ patients were older with higher body mass index (BMI) and more likely to have hypertension, renal dysfunction, and dyslipidemia. Groups were similar with respect to sex, race, CD4 count, and HIV RNA copies. N-terminal pro-B-type natriuretic peptide levels (median 36 [23, 85] vs 26 [12, 49] pg/mL, P < .01) and high-sensitivity troponin I (3.6 [2.6, 5.1] vs 2.5 [1.8, 3.5] pg/mL, P < .01) were higher among DD+ patients. The latter had similar left atrial size, but increased stiffness (conduit strain: 23.5 [17.5, 36.9] vs 30.0 [22.9, 37.0], P < .01) and impaired relaxation (reservoir strain: 39.7 [32.0, 58.0] vs 45.9 [37.0, 60.6], P = .04). On cardiac magnetic resonance, the prevalence of focal fibrosis was higher among DD+ patients (19.0% vs 5.3%, P < .01). DD+ patients demonstrated higher levels of carboxyl-terminal telopeptide of collagen type I (P = .04), and trends toward higher interleukin-6 and oxidized low-density lipoprotein levels (P ≤ .08). Kansas City Cardiomyopathy Questionnaire physical limitation (87.1±21.4 vs 93.1±18.1, P = .01) and symptom frequency scores were lower among DD+ patients (86.0±21.5 vs 92.5±16.8, P = .01).ConclusionsIn this contemporary HIV+ population receiving antiretroviral therapy, DD was associated with multiple alterations in cardiac structure and function, including myocardial fibrosis and left atrial abnormalities, and worse quality of life. Further studies are needed to assess longitudinal changes in these parameters and their potential as therapeutic targets to prevent progressive cardiac remodeling and dysfunction in HIV.

Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension (PH). However, the role of low-density lipoprotein receptor (LDL-R) in PH is not known. Methods and Results We examined the role of LDL-R in the development of PH and determined the efficacy of high-density lipoprotein mimetic peptide 4F in mitigating PH. Explanted human lungs and plasma from patients with PH and control subjects were analyzed for gene expression, histological characteristics, and lipoprotein oxidation. Male LDL-R null (LDL-R knockout) mice (12-15 months old) were fed chow, Western diet (WD), WD with 4F, and WD with scramble peptide for 12 weeks. Serial echocardiography, cardiac catheterization, oxidized LDL assay, real-time quantitative reverse transcription-polymerase chain reaction, and histological analysis were performed. The effect of LDL-R knockdown and oxidized LDL on human pulmonary artery smooth muscle cell proliferation was assessed in vitro. LDL-R and CD36 expression levels were significantly downregulated in the lungs of patients with PH. Patients with PH also had increased lung lipid deposits, oxidized LDL, E06 immunoreactivity, and plasma oxidized LDL/LDL ratio. LDL-R knockout mice on WD developed PH, right ventricular hypertrophy, right ventricular dysfunction, pulmonary vascular remodeling, fibrosis, and lipid deposition in lungs, aortic atherosclerosis, and left ventricular dysfunction, which were prevented by 4F. Interestingly, PH in WD group preceded left ventricular dysfunction. Oxidized LDL or LDL-R knockdown significantly increased proliferation of human pulmonary artery smooth muscle cells in vitro. Conclusions Human PH is associated with decreased LDL-R in lungs and increased oxidized LDL in lungs and plasma. WD-fed LDL-R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL-R and oxidized lipids in PH.

Prevalence of left ventricular (LV) systolic and diastolic dysfunction increases with aging. We previously reported that urocortin 2 (Ucn2) gene transfer increases heart function in mice with heart failure with reduced ejection fraction. Here, we test the hypotheses that (1) Ucn2 gene transfer will increase LV function in aged mice and that (2) Ucn2 gene transfer given in early life will prevent age-related LV dysfunction. Nineteen-month-old (treatment study) and 3-month-old (prevention study) mice received Ucn2 gene transfer or saline. LV function was examined 3-4 months (treatment study) or 20 months (prevention study) after Ucn2 gene transfer or saline injection. In both the treatment and prevention strategies, Ucn2 gene transfer increased ejection fraction, reduced LV volume, increased LV peak -dP/dt and peak +dP/dt, and reduced global longitudinal strain. Ucn2 gene transfer-in both treatment and prevention strategies-was associated with higher levels of LV SERCA2a protein, reduced phosphorylation of LV CaMKIIa, and reduced LV α-skeletal actin mRNA expression (reflecting reduced cardiac stress). In conclusion, Ucn2 gene transfer restores normal cardiac function in mice with age-related LV dysfunction and prevents development of LV dysfunction.

Acute ST-segment elevation myocardial infarction (STEMI) activates inflammation that can contribute to left ventricular systolic dysfunction (LVSD) and heart failure (HF). The objective of this study was to examine whether high-sensitivity C-reactive protein (CRP) concentration is predictive of long-term post-infarct LVSD and HF. In 204 patients with a first STEMI, CRP was measured at hospital admission, 24 h (CRP24), discharge (CRPDC), and 1 month after discharge (CRP1M). LVSD at 6 months after discharge (LVSD6M) and hospitalization for HF in long-term multi-year follow-up were prospectively evaluated. LVSD6M occurred in 17.6% of patients. HF hospitalization within a median follow-up of 5.6 years occurred in 45.7% of patients with LVSD6M vs. 4.9% without LVSD6M (p < 0.0001). Compared to patients without LVSD6M, the patients with LVSD6M had higher CRP24 and CRPDC and persistent CRP1M ≥ 2 mg/L. CRP levels were also higher in patients in whom LVSD persisted at 6 months (51% of all patients who had LVSD at discharge upon index STEMI) vs. patients in whom LVSD resolved. In multivariable analysis, CRP24 ≥ 19.67 mg/L improved the prediction of LVSD6M with an increased odds ratio of 1.47 (p < 0.01). Patients with LVSD6M who developed HF had the highest CRP during index STEMI. Elevated CRP concentration during STEMI can serve as a synergistic marker for risk of long-term LVSD and HF.

BACKGROUND: There is paucity of data regarding the significance of high percentage of premature ventricular contractions (PVCs) in healthy children and their impact on left ventricular (LV) function and the risk of ventricular arrhythmias. The purpose of this study was to assess the prevalence of LV systolic dysfunction in children with frequent PVCs and determine whether PVC characteristics were predictive of LV dysfunction. METHODS: We performed a single-center retrospective review to examine the prevalence of PVC-induced cardiomyopathy and natural history of PVC burden in children with frequent PVCs. Children aged 6 months-21 years with PVCs noted on 24-hr Holter monitoring studies were enrolled. The four categories included those with a PVC burden of >10%, 10%-20%, and those with more than 20% PVC burden. RESULTS: A total of 134 children were included, 65 with more than 10% PVCs and 31 with more than 20% PVCs. Median age of the patients was 10.5 years (IQR 6.1-14.8 years), with 79 males (54.5%). Median PVC burden was 8.7% (IQR 4.2%-16.9%) with median follow-up of 2.8 years (IQR 1.2-4.6 years). During 2.8 years (1.3-4.3 years) of follow-up, the PVC burden decreased by 67% of baseline PVC burden in those who did not undergo any intervention. There were no deaths. CONCLUSION: PVCs in children with structurally normal hearts are associated with a relatively benign course, with trend toward spontaneous resolution.

Various forms of vortex formation in the cardiovascular system convey valuable information regarding the function of heart and great vessels. The vortex ring that forms during systole in the aortic sinus is the first that was recognized and the asymmetric transmitral vortex ring that forms in the left ventricle during diastole has been most commonly used for diagnosis and follow up of heart failure patients. Adverse vortex interaction in the heart can also occur due to valvular regurgitation and may have energetic consequences to the heart. Furthermore, vortices do exist in other chambers such as the right ventricle and may even arise in the great arteries and veins due to congenital heart disease. Here, we summarize diagnostic and prognostic significance of vortices and vortex imaging in the heart, their applications in clinical medicine, and discuss how these flow features can be used to assess functional status of the heart.

BACKGROUND: National guidelines recommend that systolic blood pressure (SBP) in patients with heart failure with reduced ejection fraction (HFrEF) and hypertension be maintained below 130 mm Hg. OBJECTIVES: This study sought to determine associations of SBP

Right ventricular dysfunction is highly prevalent across cardiopulmonary diseases and independently predicts death in both heart failure (HF) and pulmonary hypertension (PH). Progression towards right ventricular failure (RVF) can occur in spite of optimal medical treatment of HF or PH, highlighting current insufficient understanding of RVF molecular pathophysiology. To identify molecular mechanisms that may distinctly underlie RVF, we investigated the cardiac ventricular transcriptome of advanced HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, we identified an RVF-specific gene module, for which WIPI1 served as a hub and HSPB6 and MAP4 as drivers, and confirmed the ventricular specificity of Wipi1, Hspb6, and Map4 transcriptional changes in adult murine models of pressure overload induced RV- versus LV- failure. We uncovered a shift towards non-canonical autophagy in the failing RV that correlated with RV-specific Wipi1 upregulation. In vitro siRNA silencing of Wipi1 in neonatal rat ventricular myocytes limited non-canonical autophagy and blunted aldosterone-induced mitochondrial superoxide levels. Our findings suggest that Wipi1 regulates mitochondrial oxidative signaling and non-canonical autophagy in cardiac myocytes. Together with our human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render Wipi1 a potential target for RV-directed HF therapy.

PurposeHER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction.MethodsPatients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%.ResultsOf 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%.ConclusionThis study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

ObjectivesTo evaluate whether the presence of preexisting right ventricular (RV) dysfunction in high-risk patients undergoing nonemergent major vascular surgery is associated independently with higher incidents of postoperative cardiac complications and a longer length of hospital stay.DesignRetrospective chart review.SettingSingle-center university hospital setting.ParticipantsThe patient population consisted of those identified as American Society of Anesthesiologists classification III and above who had a preoperative echocardiogram within 1 year of undergoing nonemergent major vascular surgery between January 2010 and May 2017.Measurements and main resultsAfter multivariate analyses, RV dysfunction (RVD) is associated independently with a higher incidence of postoperative major cardiac complications with an odds ratio = 6.3 (95% confidence interval [CI], 1.0-38.5; p = 0.046). In addition, patients with RVD had a 50% longer length of stay than those without RVD (incident rate ratio [95% CI], 1.5 [1.2-1.8]; p < 0.001).ConclusionIn this retrospective study of high-risk patients undergoing major vascular surgery, RV dysfunction was associated independently with a higher incidence of postoperative major cardiovascular events and longer length of hospital stays. Based on current findings, the prognostic value of RVD extends beyond the cardiac surgical cohort. Knowledge in management of patients with RVD in the perioperative setting should be understood by all anesthesiologists. Of note, a future study with a larger sample size is needed to validate the current findings given the small sample size of this study.

BackgroundGuidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) have medical therapy titrated to target doses derived from clinical trials, as tolerated. The degree to which titration occurs in contemporary U.S. practice is unknown.ObjectivesThis study sought to characterize longitudinal titration of HFrEF medical therapy in clinical practice and to identify associated factors and reasons for medication changes.MethodsAmong 2,588 U.S. outpatients with chronic HFrEF in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry with complete medication data and no contraindications to medical therapy, use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) were examined at baseline and at 12-month follow-up.ResultsAt baseline, 658 (25%), 525 (20%), 287 (11%), and 45 (2%) patients were receiving target doses of MRA, beta-blocker, ACEI/ARB, and ARNI therapy, respectively. At 12 months, proportions of patients with medication initiation or dose increase were 6% for MRA, 10% for beta-blocker, 7% for ACEI/ARB, and 10% for ARNI; corresponding proportions with discontinuation or dose decrease were 4%, 7%, 11%, and 3%, respectively. Over 12 months,

BackgroundDiastolic dysfunction (DD) identified on echocardiography predicts mortality after cardiac surgery, however the most useful diastolic parameters for assessment and the association of DD with prolonged mechanical ventilation, ICU re-admission, and hospital length of stay are not established.MethodsWe included patients that underwent coronary artery bypass grafting (CABG), aortic valve replacement (AVR) or a combined procedure (CAB-AVR) from 2010 to 2016, and who had preoperative transthoracic echocardiography (TTE) at our institution within 6 months of the operation. Diastolic function was graded using the transmitral E and A waves and the septal tissue Doppler velocity. We performed logistic regression to assess the association of grade of DD with a composite endpoint of death, prolonged mechanical ventilation, ICU readmission during hospitalization, and hospital length of stay longer than 14 days.ResultsBetween 2010 and 2016, 577 patients were eligible for inclusion. DD was common, with 42% of the cohort manifesting grade II or grade III DD. Rates of death and prolonged ventilation increased across grades of DD and across quartiles of increasing LV filling pressure, assessed by the E/e' ratio. Adjusting for age, sex, procedure, systolic and diastolic function, both systolic (odds ratio 0.68 95% CI 0.55-0.85 per inter-quartile increase in LVEF) and diastolic function (odds ratio 1.31 95% CI 1.04-1.66 per increasing DD grade) both independently predicted outcome.ConclusionDiastolic dysfunction is common among patients undergoing cardiac surgery and is associated with death, prolonged mechanical ventilation, and prolonged hospital and ICU length of stay independent of systolic dysfunction.

BackgroundRight ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies.MethodsA multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations.ResultsThis document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes.ConclusionsThis statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.